title: Investigating the role of tbx4 in the female germline in mice.
abstract: Normal development of germ cells is essential for fertility and mammalian reproduction. Although abnormal development of oocytes or follicles may lead to primary ovarian insufficiency (POI), a disorder that causes infertility in 1% of women less than 40 yr of age, the genes and signaling pathways activated in POI are not as yet fully elucidated. Tbx4, a member of the T-box family of transcription factors, is expressed in embryonic germ cells and postnatal oocytes at all stages of folliculogenesis. To investigate the requirement for Tbx4 in the germline, we analyzed germ cell development in the absence of Tbx4. We show that primordial germ cells (PGCs) are reduced in Tbx4 homozygous null (Tbx4(-/-)) embryos at Embryonic Day (E) 10.0. Tbx4(-/-) embryos die by E10.5; to study later time points in vitro, a tamoxifen-inducible estrogen receptor Cre recombinase was used to delete Tbx4 conditional mutant alleles. In addition, Gdf9cre and Zp3cre, two oocyte-specific Cre recombinases, were used to delete Tbx4 from postnatal primordial and primary follicles, respectively. We show that in vitro differentiation of the gonad into morphologically distinct testes and ovaries occurs normally starting at E11.5 when Tbx4 is deleted. In Gdf9cre; Tbx4(fl/-) and Zp3cre; Tbx4(fl/-) adult females, primordial, primary, secondary, and antral follicles form, ovulation occurs, corpus luteum formation is normal, and the mice are fertile without any evidence of diminished ovarian reserve. Although postnatal deletion of Tbx4 in oocytes does not obviously impair fertility, it is possible that the reduction in PGCs observed in Tbx4 homozygous null mutant embryos could affect long-term fertility in adults.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Columbia University Medical Center, New York, New York.
authors.forename: Nataki C
authors.initials: NC
authors.lastname: Douglas
authors.forename: Ripla
authors.initials: R
authors.lastname: Arora
authors.forename: Cayla Yiyu
authors.initials: CY
authors.lastname: Chen
authors.forename: Mark V
authors.initials: MV
authors.lastname: Sauer
authors.forename: Virginia E
authors.initials: VE
authors.lastname: Papaioannou
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009865:Oocytes / Q000166:cytology / Q000378:metabolism*; D010053:Ovary / Q000166:cytology / Q000378:metabolism; D011247:Pregnancy; D020825:T-Box Domain Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D020825:T-Box Domain Proteins; C103177:Tbx4 protein, mouse
keywords: T-box; Tbx4; fertility; oocytes; primordial germ cells